Alpha-(4-cyano-4-aryl-1-cyclohexenyl)-propionic acids and esters

ABSTRACT

ARYLCYCLOHEXENYL COMPOUNDS OF THE FORMULA   1-(X-CO-C(-R1)(-R2)-),4-R3,4-R4-CYCLOHEXENE   WHEREIN R1 IS HYDROGEN OR LOWER ALKYL, R2 IS LOWER ALKYL, R3 IS HYDROGEN, LOWER ALKYL, PHENYL, CYANO OR TRIFLUOROMETHYL, R4 IS NAPHTHYL, PHENYL, HALOPHENYL, LOWER-ALKOXYLPHENYL, LOWER-ALKOXY-PHENYL, TRIFLUOROMETHYLPHENYL, ALKYLENEDIOXYPHENYL, OR BIPHENYLYL, AND X IS LOWER ALKOXY, HYDROXYL, AMINO, HYDROXYLAMINO, OR OWER-ALKYLAMINO. THESE COMPOUNDS POSSESS ANTI-INFLAMMATORY, THROMBOLYTIC AND/OR FIBRINOLYTIC PROPERTIES.

United States Patent Us. Cl. 260-465 D 9 Claims ABSTRACT OF THEDISCLOSURE Arylcyclohexenyl compounds of the formula The presentinvention provides arylcyclohexenyl compounds of the General Formula Iwherein:

R is selected from the group consisting of a hydrogen atom and linearand branched lower alkyl radicals containing from 1 to 6 carbon atomsinclusive;

R is selected from the group consisting of linear and branched loweralkyl radicals containing from 1 to 6 carbon atoms inclusive;

R is selected from the group consisting of a hydrogen atom, linear andbranched lower alkyl radicals containing from 1 to 6 carbon atomsinclusive, a phenyl radical, a cyano radical and a trifl-uoromethylradical;

R is selected from the group consisting of a naphthyl I radical, anunsubstituted phenyl radical and phenyl.

radicals mono and poly substituted by: halogen atoms, linear andbranched lower alkyl and lower alkoxy radicals each containing from 1 to6 carbon atoms inclusive, trifluoromethyl radicals, alkylenedioxyradicals containing 1 and 2 carbon atoms, and phenyl radicals; and X isselected from the group consisting of linear and branched lower alkoxyradicals containing from 1 to 6 carbon atoms inclusive, a hydroxylradical, an amino radical, a hydroxylamino radical and alower-alkylamino radical wherein the alkyl moiety has from 1 to 6 carbonatoms inclusive.

The new compounds of the General Formula I are prepared by submitting tothe Reformatsky reaction a cyclohexanone of the General Formula IIwherein R and R have the meanings given above, and an a-bromo ester ofthe General Formula III 3,803,203 Patented Apr. 9, 1974 I in which R,and R have the meanings given above, and R represents a lower alkoxyradical containing from 1 to 6 carbon atoms inclusive in a linear orbranched chain. The resulting hydroxylated compound of the GeneralFormula IV wherein R, R R R and R have the meanings given above,

is then dehydrated by a method known per se, for example, by the methoddescribed by G. A. R Kon and K. S. Nargund [cf. 1. Chem. Soc., 2461(1932)], to yield a compound of the General Formula I, wherein X is alower alkoxy radical containing from 1 to 6 carbon atoms inclusive in alinear or branched chain. This last mentioned compound is then reactedwith a compound of the General Formula HX, wherein X has the abovedefined meanings except a lower alkoxy radical, in order to obtain theother compounds of the General Formula I.

The starting cyclohexanones oi the General Formula II are prepared by amethod known per se, for example by one of the methods described by F.G. Bordwell et al. [cl-T. J. Amer. Chem. Soc., 89, 6704 (1967)] and E.C. Horning et al. [cf. J. Amer. Chem. Soc., 74, 173 (1952)].

The compounds of the General Formula I wherein X is a hydroxyl or ahydroxylamino radical, may be concerted into addition salts with mineralbases for example bases of alkali or alkaline earth metals, for examplesodium, potassium or calcium hydroxide, carbonate or bicarbonate, orwith organic bases, for example primary, secondary or tertiary amines,for example mono-, dior triethylamine, alkanolamines, or dialkylaminoalkanols. The compounds of the General Formula I wherein X is a basicradical may be converted into addition salts with mineral or organicacids, for example hydrochloric, hydrobromic, sulphuric, phosphoric,acetic, propionic, maleic, tartric, citric, oxalic and benzoic acids.All these salts are included in the present invention.

Most of the compounds of the present invention contain one asymmetriccarbon atom and may be resolved, by a method known per se, into opticalisomers which are also included in the present invention.

The following examples illustrate the invention, the melting pointsbeing determined in a capillary tube, unless otherwise stated.

EXAMPLE 1 Ethyl a-(4-methyl-4-phenyl-1-cyclohexen-1-yl)- propionateCH-COOCzE A /3 of a solution (a), containing 16.3 g. (0.09 mol) ofethyla-bromopropionate, 16.9 g. (0.09 mol) of4-methyl-4-pheny1-cyclohexanone, and 50 ml. of anhydrous benzene wasadded to 5.9 g. (0.09 mol) of zinc cuttings in the presence of somemercuric chloride crystals and an iodine crystal. The Reformatskyreaction was started with a slight heating and the remaining of thesolution (a) was dropped into the reaction mixture maintained at theboiling point. The heating under reflux was maintained for three hoursafter the completion of the addition, then the reaction mixture cooledto the room temperature was poured on 77 g. of cracked ice and 49 ml. ofacetic acid.

The benzenic layer was washed with an aqueous solution of sodiumbicarbonate, then with distilled water until neutral. After drying oncalcium sulphate and filtration, the solution was concentrated todryness and the residue was distilled under vacuum. 17.4 g. of a mixtureof ethyl a-(4-methyl-4-phenyl-1-hydroxy-cyclohexyl) propionate cis andtrans isomers were obtained (B.P./ 0.02 mm. Hg: 130-134 C., yield 67%).

A mixture comprising 17.4 g. (0.06 mol) of the above ester, 55 ml. ofbenzene and 106 g. (0.075 mol) of phosphoric anhydride was stirred atreflux for 4 hours. After pouring 01f the benzene layer was distilledunder reduced pressure. 11.2 g. of ethyla-(4-methyl-4-phenyl-I-cyclohexen-1-yl)-propionate were obtained.(B.P./0.005 mm. Hg: 117-1l9 C., yield 68.8%).

EXAMPLES 2-4 The following compounds were prepared according to themethod described in Example 1:

(2) Ethyl u-(4-phenyl-l-cyclohexen-l-yl)-propionate, B.P./0.02 mm. Hg:106-108 C., starting from crude ethyl a-(4-phenyl 1hydroxy-cyclohexyl)-propionate, yield 61%, itself prepared from4-phenyl-cyclohexanone and ethyl a-bromopropionate, yield 83.2%.

(3) Ethyl a-(4-cyano 4 orthochlorophenyl-l-cyclohexen-1-yl)-propionate,B.P./0.1 mm. Hg: 210-214 C., starting from crude ethyl-u-(4-cyano-4-orthochlorophenyl-l-hydroxy-cyclohexyl)-propionate, yield:37.8%, itself prepared from 4-cyano-4-orthochlorophenyl-cyclohexanoneand ethyl a-bromopropionate, yield: 92.5%

(4) Ethyl a-(4,4-diphenyl 1 cyclohexen-l-yl)-propionate, B.P./0.02 mm.Hg: 181-182 C., starting from crude ethyla(4,4-diphenyl-l-hydroxy-cyclohexyl)-propionate, yield: 54.8%, itselfprepared from 4,4-diphenylcyclohexanone and ethyl a-bromopropionate,yield: 91%.

EXAMPLE 5 q-(4-methyl-4-phenyl-l-cyclohexen-l-yl)-propioni acid CaHiCH-CO OH taken out with ether. The ethereal solution was washedwithdistilled water, dried on calcium sulphate, filtrated and concentratedto dryness. 8.5 g. of u-(4-methyl-4- phenyl-l-cyclohexen-l-yl)-propionicacid were obtained (yield: 84.5% This product was purified bydistillation (B.P./0.05 mm. Hg: 150-154" C., M.P. 52-54 C., yield of thepurification: 70%

EXAMPLES 6-30 .The following compounds were prepared according to themethod described in Example 5:

(6) m-(4-phenyl-1-cyclohexen 1-yl)-propionic acid, M.P. 90-91 C.,starting from ethyl ot-(4cyano-4-cyclohergen-l-yl) -propionate describedin Example 2, yield 90 0.

(7) a-(4-cyano-4-orthochlorophenyl l-cyclohexen-lyl)-propionic acid,M.P. 136-140 C., starting from ethyl.

a-(4-cyano-4-orthochlorophenyl 1 cyclohexen-1-yl)- propionate describedin Example 3, yield 78%.

(8) u-(4,4-diphenyl-l-cyclohexen 1 yl)-propionic acid, M.P. (Kofler)126-127 C., starting from ethyl a-(4,4-diphenyl 1cyclohexen-l-yl)-propionate described in Example 4, yield 90%.

(9) a-(4-orthochlorophenyl-l-cyclohexen 1-yl)-pr0- pionic acid, M.P.60-62 C., starting from ethyl d-(4- orthochlorophenyl-l-cyclohexen1-yl)-propionate, B.P./ 0.05 mm. Hg: 148-150 C., yield 92.5%, itselfprepared from crude ethyla-(4-orthochlorophenyl-l-hydroxy-cyclohexyl)-propionate, yield 50%,prepared from 4-orthochlorophenyl-cyclohexanone and ethyla-bromopropionate, yied 82.5%.

(10) a-(4-paramethoxyphenyl 1 cyclohexen-1-yl)- propionic acid, M.P.(Kofler) 110-112 C., starting from ethylu-(4-paramethoxyphenyl-l-cyclohexen 1-y1)-propionate, B.P./0.3 mm. Hg:178184 C., yield 45%, itself prepared from crude ethyl oz-(4-paramethoxyphenyll-hydroxy-cyclohexyl)-propionate, yield 77%,prepared from 4-paramethoxyphenyl-cyclohexanone and ethyl u.-bromopropionate, yield 82.5

(11) a-[4-(3,4-methylenedioxyphenyl) l-cyclohexen- 1-yl]-propionic acid,M.P. (Kofler) 130 C., starting from ethyl a-[4-(3,4methylenedioxyphenyl)-l-cyclohexen-l-yl]-propionate, B.P./0.04 mm. Hg:170-180 C., yield 73.6%, itself prepared from crude ethyl u-[4-(3,4-methylenedioxyphenyl) 1 hydroxy-cyclohexyl)-propionate, yield 63%,prepared from 4-(3,4-methylenedioxyphenyl)-cyclohexanone and ethyla-bromo-propionate, yield 100%.

(12) a-(4-parafluorophenyl l-cyclohexen-l-yD-propionic acid, M.P.(Kofler) 110-1l2 C., starting from ethyl m-(4-para-fiuorophenyl-1cyclohexen-1-yl)-propionate, B.P.: 190-200" C., yield 64%, itselfprepared from crude ethyl a-(4-parafluorophenyl-1hydroxy-cyclohexyl)-propionate, yield 48%, prepared from4-parafluorophenylcyclohexanone and ethyl a-bromopropionate, yield 98%.

(13) a-(4-orthofiuorophenyl-4-cyano 1 cyclohexenl-yl)-propionic acid,M.P. (Kofler) 116-118 C., starting from ethylu-(4-orthofluorophenyl-4-cyano-l-cyclohexen-1-yl)-propionate, B.P./ 0.05mm. Hg: 180-200 C., yield 40%, itself prepared from crude ethyl a-(4-orthofluorophenyl 4 cyano 1 hydroxy-cyclohexyl)- propionate, yield 43%,prepared from 4-orthofluorophenyl-4-cyano-cyclohexanone and ethylm-bromopropionate, yield 80.5%.

(14) a-[4-(1-naphtyl) 4 cyano-l-cyclohexen-l-yl]- propionic acid, M.P.(Kofler) 164-165 C., starting from ethyl a-[4-(1-naphthyl)-4-cyanol-cyclohexen-1- yl]-propionate, B.P./O.3 mm. Hg: 210-240 C., yield 41%,itself prepared from crude ethyl a-[4-(1-naphtyl)-4-cyano-1-hydroxy-cyclohexyl)-propionate, yield 44.5%, prepared from4-(l-naphtyl)-4-cyano-cyclohexanone and ethyl a-bromopropionate, yield93.5%.

(15) a-(4-para-fluorophenyl 4 cyano-l-cyclohexen- 1-yl)-propionic acid,M.P. (Kofler) 85 C., starting from ethyl a-(4-parafluorophenyl 4cyano-l-cyclohexen-lyl)-propionate, B.P./0.05 mm. Hg: -190 C., yield34%, itself prepared from ethyl a-(4-parafluorophenyl- 4-cyano-1hydroxy-cyclohexyl)-propionate, B.P./0.05 mm. Hg: 200 C., yield 64%,prepared from 4-parafiuorophenyl-4-cyano-cyclohexanone and ethyla-bromoprop ibhate, yield 50.5%.

(l6) u-(4-metachlorophenyl 4 cyano-l-cyclohexen- 1-yl)-propionic acid,M.P. (Kofler) 90 C., starting from ethyl u-(4-metachlorophenyl 4cyano-l-cyclohexenl-yl)-propionate, B.P./0.1 mm. Hg: 200 C., yield37.5%, itself prepared from crude ethyl m-(4-metachlorophenyl-4-cyano-1-hydroxy-cyclohexyl)-propionate, yield 47%, prepared from4-metachlorophenyl 4-cyano-cyclohexanone and ethyl a-bromopropionate,yield 99%.

(17) a-(4-phenyl-4-cyano 1 cycl0hexen-1-yl)-propionic acid, M.P.(Kofler) 90-92 C., starting from ethyl u-(4-phenyl-4-cyano 1cyclohexen-1-yl)-propionate, B.P./0.05 mm. Hg: 180190' C., yield 35%,itself prepared from crude ethyla-(4-phenyl-4-cyano-1-hydroxycyclohexyl)-propionate, yield 38%, preparedfrom 4- phenyl-4-cyano-cyclohexanone and ethyl a-bromopropionate, yield97.5

3 (18) e-(4-orthotrifluoromethylphenyl 4cyano-l-cyclohexen-1-yl)-propionic acid, M.P. (Kofier) 110-112 C.,starting from ethyl e-(4-orthotrifluoromethylphenyl-4-cyano-l-cyclohexen-l-yl) propionate, B.P./0.05 mm. Hg: 180-200" C.,yield 34%, itself prepared from crude ethyle-(4-orthotrifluoromethylphenyl 4cyano-l-hydroxy-cyclohexyl)-propionate, yield 53%, prepared from4-orthotrifiuoromethylphenyl' 4 cyano-cyclohexanon and ethyla-bromopropionate, yield 94%.

(19) e-[4-(3,4-methylenedioxyphenyl)-4-methyl 1-vcyclohexen-l-yl]-propionic acid, M.P. (Kofier) 90 C., starting from;ethyl tat-[4-(3,4-methylenedioxphenyl)-4-methyl-l-cyclohexenl-yll-propionate, B.P./0.05 mm. Hg: 175 C., yield84.5%, itself prepared from crude ethyl m-[4-(3,4-methylenedioxyphenyl)4 methyl-l-hydroxy-cyclohexyl]-propionate, yield 75%, prepared from4-(3,4-methylenedioxyphenyl) 4-methylcyclohexanone and ethyla-bI'OmOpI'OPiOnatC, yield 99%.

(20) a-(4-paramethylphenyl-4-methyl l-cyclohexen- 1-yl)-propionic acid,M.P. 51-53" 0., starting from ethyl a-(4-paramethylphenyl 4methyl-l-cyclohexen-l-yl)- propionate, B.P./0.05 mm. Hg: 138-140 C.,yield 70%, itself prepared from crude ethyl u-(4-biphenyl-4-methyl-4-methyl-l-hydroxy-cyclohexyl)-propionate, yield 43.5%, prepared from4-paramethylphenyl-4-methyl-cyclohexanone and ethyl a-bromopropionate,yield 96%.

(21) a-(4-biphenyl 4 methyl-l-cyclohexen-1-yl)- propionic acid, M.P.(Kofier) 118119 C., starting from ethyl a-(4 biphenyl-4-methyl 1cyclohexen-l-yD-propionate, B.P./0.01 mm. Hg: 215-220 C., yield 74%,itself prepared from crude et-hyla-(4biphcnyl-4-methyll-hydroxy-cyclohexyl)-propionate, yield 66%,prepared from 4-biphenylyl-4-methyl-cyclohexanone and ethylabromopropionate, yield 99%.

(22) a-[4-(1-naphthyl) 4 methyl-l-cyclohexen-lyl]-propionic acid, M.P.136-138" C., starting from ethyl ot-[4-(l-naphthyl) 4methyl-l-cyclohexen-l-yH-pro-' pionate, B.P./0.05 mm. Hg: 198-200 C.,yield 62%, itself prepared from crude ethyl a-[4-(1-naphthyl)-4- methyl1 hydroxy-cyclohexyl]-propionate, yield 50%, prepared from4-(l-naphthyl)-4-methyl-cyclohexanone and ethyl a-bromopropionate, yield95.5%.

(23) a-(4-paramethoxyphenyl 4 methyl-l-cyclohexen-1-yl)-propionic acid,isolated as a sodium salt, starting from ethyla-(4-paramethoxyphenyl-4-methyl-l-cyclohexen-1-yl)-propionate, B.P./0.1mm. Hg: 160 0., yield 76%, itself prepared from crude ethyla-(4-paramethoxyphenyl 4 methyl-1-hydroxy-cyclohexyl) -propionate, yield67%, prepared from 4-paramethoxyphenyl-4-methyl-cyclohexanone and ethyla-bromopropionate, yield 93%.

(24) a-(4-biphenylyl 4 cyano 1 cyclohexen-1-yl)- propionic acid, M.P.(Kofier) 140-141 0., starting from ethyl a-(4-biphenylyl-4-cyano 1cyclohexen-1-yl)-propionate, B.P./0.1 mm. Hg: 250 C., yield 34%, itselfprepared from crude ethyl u-(4-biphenylyl-4-cyano-l-hydroxy cyclohexyl)propionate, yield 50.5%, prepared from4-biphenylyl-4-cyano-cyclohexanone and ethyl ubromopropionate, yield100%.

(25) tat-(4 parachlorophenyl 4 cyano-l-cyclohexen- 1-yl)-propionic acid,M.P. (Kofier) 119-120" C., starting from ethyla-(4-parachlorophenyl-4-cyano-l-cyclohexen-1-yl)-propionate, B.P./0.05mm. Hg: ZOO-218 C., yield 25%, itself prepared from crude ethyla-(4-parachlorophenyl 4 cyano 1 hydroxy-cyclohexyl)-propionate, yield43.5%, prepared from 4-parachlorophenyl- 4-cyano-cyclohexanone and ethylu-bromopropionate, yield 90%.

(26) o:- (4 paratrifluoromethylphenyl-l-cyclohexen- 1-yl)-a-methylpropanoic acid, starting from ethyl G-(4- paratrifluoromethylphenyl 1cycIQheXen-I-yD-u-methyl propanoate, itself prepared from ethyla-(4-paratriflueromethylphenyl 1 hydroxy-cyclohexylyet-methylpropanoate,prepared from 4-paratrifluoromethylphenylcyclohexanone and ethyla-bromo-a-methyl propanoate.

(27) v r-(4 --phenyl 4 trifiuoromethyl-l-cyclohexen- 1-yl)-a-methylpropanoic acid, starting from ethyl a- (4-phenyl 4trifluoromethyl-l-cyclohexen-l-yD-amethyl propanoate, itself preparedfrom ethyl u-(4-phen yl-4-trifluoromethyl 1 hydroxy-cyclohexyl)-a-methylpropanoate, prepared from 4-phenyl-4-trifiuoromethyl-cyclohexanone' andethyl u-bromo-a-methyl propanoate.

' (28) a-(4 phenyl l cyclohexen-1-yl)-propionamide, starting from ethyla-(4-phenyl-l-cyclohexen-lyl)-propionate, described in Example 2, and anammoniacal solution in place of sodium hydroxide.

(29) N-methyl oz-(4 phenyl 1 cyclohexen-1-yl)- propionamide, startingfrom ethyl a-(4-phenyl-1-cyclo hexen-1-yl)-propionate, described inExample 2, and a monomethylamine solution in place of sodium hydroxide.

(30) (x-(4 phenyl 4 methyl-l-cyclohexen-1-yl)-propionohydroxamic acid,starting from ethyl a-(4-phenyl- 4-methyl-1-cyclohexen-1-yl)-propionate,described in Example 7, and a hydroxylamine solution in place of sodiumhydroxide).

The compounds of the present invention and the physiologically tolerableaddition salts thereof possess valuable pharmacological and therapeuticproperties, especially anti-inflammatory, thrombolytic and/orfibrinolytic properties.

The toxicity of these compounds is weak. Their LD in mice is between 500and 1000 mg./ kg. by oral route.

The anti-inflammatory activity was evidenced by the method of C. A.Winter et al. (Proc. Soc. Exp. Biol. Med., 3, 544, 1962) on the plantaredema of the rats paw, induced by carrageenin. It was found that 40 tomg./kg. of the new compounds administered per os decrease by 6 to 70%this type of inflammation. This same activity was demonstrated also onthe ultraviolet rayinduced erythema, which is inhibited from 30 to 60%by 50 to 75 mg./kg. of the new compounds.

The thrombolytic activity was studied in vitro by the method of VonKaulla (Thromb. Diath. Haem., 5, 489 1961) on the standard blod clot. Iswas observed that the new compounds provoke the lysis of the blood clotat molar concentration of 0.01 to 0.007 corresponding to concentrationof 0.01 to 0.007 corresponding to concentrations of 12.93 to 1.32mg./ml. It was also observed that the new compounds possess fibrinolyticproperties, decreasing, at doses of 10 to mg./kg. per os, from 5 to 20%the euglobulin lysis time, 30 to minutes after administration.

The low toxicity and the here-above described pharmacological propertiesallow the use of the compounds of the present invention in therapy,especially in the prevention and the treatment of inflammation,polyarthritis, rheumatisms and thromboembolic diseases.

The present invention also provides pharmaceutical compositions,containing a compound of General Formula I or a physiologicallytolerable salt thereof in admixture or conjunction with a suitablepharmaceutical carrier, such, for example, as distilled water, glucose,lactose, talc, starch, magnesium stearate and cocoa-butter.

The pharmaceutical compositions may be in the form of tablets, drages,capsules, suppositories or solutions for injection, in order to beadministered by oral, rectal or parenteral route, at doses of 50 to 500mg., 1 to 5 times a day.

What we claim is:

1. A compound selected from the group consisting of:

(a) arylcyclohexenyl compounds of the formula NC Me wherein:

R is hydrogen or methyl,

R is phenyl, halophenyl, biphenyl, trifluoromethylphenyl or naphth'yl,and

X is hydroxyl or ethoxy; and

(b) physiologically tolerable addition salts with mineral or organicbases when X is hydroxyl.

2. A compound of claim 1 which is u-[4-(1-naphthyl-)- 4-cyano-lcyclohexen-1-yl]-propionic acid.

6. A compound of claim 1 which isa-(4-orothofluoropheny1-4cyano-l-dyclohexen-l-yl)-propionic acid. i

4. a-(4-cyano 4 orthochlorophenyl-l-cyclohexen-lyD-propionic acid,according to. claim 1.

5. a-(4 metachlorophenyl 4 cyano-l-cyclohexen-lyl)-propionic acid,according to claim 1 6. a-(4 phenyl 4 cyano-lrcyclohexen-l-yl)-propionicacid, according to claiml.

7. a-(4-orthotrifluoromethylphenyl 4 cyano-d-cyclohexen-l-yD-propionicacid, according to claim 1.

- 8. oz-(4 biphenyl-4-cyano-l-cyclohexen-l-y1)-propi0nic acid, accordingto claim 1.

9. oz-(4 parachlorophenyl 4 cyano-l-cyclohexen-lyl)-propionic acid,according to claim 1.

I References Cited UNITED STATES PATENTS 3,452,079 6/1969 Shen et al.260-465 X LEWIS GO'ITS, Primary Examiner D. H. TORLRENCE, AssistantExaminer US. Cl. X.R.

15 2'60469, 515 A, 515 R, 558 R;424 304, 308, 317, 324

